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CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis



This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer.


We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin–CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model.


CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK–MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model.


CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.

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  1. Anderberg C et al (2013) Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210:563–579. https://doi.org/10.1084/jem.20120662

  2. Bartley TD et al (1994) Identification and cloning of a megakaryocyte growth and development factor that is a ligand for the cytokine receptor. MpI Cell 77:1117–1124. https://doi.org/10.1016/0092-8674(94)90450-2

  3. Besancenot R et al (2010) A senescence-like cell-cycle arrest occurs during megakaryocytic maturation: implications for physiological and pathological megakaryocytic proliferation PLoS Biol. https://doi.org/10.1371/journal.pbio.1000476

  4. Besancenot R et al (2014) JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation. Blood 124:2104–2115. https://doi.org/10.1182/blood-2014-03-559815

  5. Chabottaux V et al (2009) Membrane-type 4 matrix metalloproteinase (MT4-MMP) induces lung metastasis by alteration of primary breast tumour vascular architecture. J Cell Mol Med 13:4002–4013. https://doi.org/10.1111/j.1582-4934.2009.00764.x

  6. Chanprasert S, Geddis AE, Barroga C, Fox NE, Kaushansky K (2006) Thrombopoietin (TPO) induces c-myc expression through a PI3K- and MAPK-dependent pathway that is not mediated by Akt, PKCzeta or mTOR in TPO-dependent cell lines and primary megakaryocytes. Cell Signal 18:1212–1218. https://doi.org/10.1016/j.cellsig.2005.09.010

  7. Chijiiwa Y et al (2016) Overexpression of microRNA-5100 decreases the aggressive phenotype of pancreatic cancer cells by targeting PODXL. Int J Oncol 48:1688–1700. https://doi.org/10.3892/ijo.2016.3389

  8. Choi C, Helfman DM (2014) The Ras-ERK pathway modulates cytoskeleton organization, cell motility and lung metastasis signature genes in MDA-MB-231. LM2 Oncogene 33:3668–3676. https://doi.org/10.1038/onc.2013.341

  9. Dong-Feng Z, Ting L, Yong Z, Cheng C, Xi Z, Pei-Yan K (2014) The TPO/c-MPL pathway in the bone marrow may protect leukemia cells from chemotherapy in AML Patients. Pathol Oncol Res 20:309–317. https://doi.org/10.1007/s12253-013-9696-z

  10. Dorsch M, Fan P-D, Danial NN, Rothman PB, Goff SP (1997) The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. J Exp Med 186:1947–1955

  11. Elf S et al (2016) Mutant calreticulin requires both its mutant C-terminus and the thrombopoietin receptor for oncogenic transformation. Cancer Discov 6:368–381. https://doi.org/10.1158/2159-8290.CD-15-1434

  12. Engl T et al (2006) CXCR4 chemokine receptor mediates prostate tumor cell adhesion through alpha5 and beta3 integrins. Neoplasia 8:290–301. https://doi.org/10.1593/neo.05694

  13. Gao W, Chen L, Ma Z, Du Z, Zhao Z, Hu Z, Li Q (2013) Isolation and phenotypic characterization of colorectal cancer stem cells with organ-specific metastatic potential. Gastroenterology 145:636–646 e635. https://doi.org/10.1053/j.gastro.2013.05.049

  14. Gleisner AL et al (2007) Is resection of periampullary or pancreatic adenocarcinoma with synchronous hepatic metastasis justified? Cancer 110:2484–2492. https://doi.org/10.1002/cncr.23074

  15. Goetz JG et al (2011) Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146:148–163. https://doi.org/10.1016/j.cell.2011.05.040

  16. Hayes TK et al (2016) Long-term ERK Inhibition in KRAS-mutant pancreatic cancer is associated with myc degradation and senescence-like growth suppression. Cancer Cell 29:75–89. https://doi.org/10.1016/j.ccell.2015.11.011

  17. Hess KR, Varadhachary GR, Taylor SH, Wei W, Raber MN, Lenzi R, Abbruzzese JL (2006) Metastatic patterns in adenocarcinoma. Cancer 106:1624–1633. https://doi.org/10.1002/cncr.21778

  18. Hitchcock IS, Kaushansky K (2014) Thrombopoietin from beginning to end. Br J Haematol 165:259–268. https://doi.org/10.1111/bjh.12772

  19. Kaushansky K (2005) The molecular mechanisms that control thrombopoiesis. J Clin Invest 115:3339–3347. https://doi.org/10.1172/JCI26674

  20. Kaushansky K (2006) Lineage-specific hematopoietic growth factors. N Engl J Med 354:2034–2045. https://doi.org/10.1056/NEJMra052706

  21. Kukreja P, Abdel-Mageed AB, Mondal D, Liu K, Agrawal KC (2005) Up-regulation of CXCR4 expression in PC-3 cells by stromal-derived factor-1alpha (CXCL12) increases endothelial adhesion and transendothelial migration: role of MEK/ERK signaling pathway-dependent NF-kappaB activation. Cancer Res 65:9891–9898. https://doi.org/10.1158/0008-5472.CAN-05-1293

  22. Lin WC et al (2013) Dormant cancer cells contribute to residual disease in a model of reversible pancreatic cancer. Cancer Res 73:1821–1830. https://doi.org/10.1158/0008-5472.CAN-12-2067

  23. Lok S et al (1994) Cloning and expression of murine thrombopoietin cDNA and stimulation of platelet production in vivo. Nature 369:565. https://doi.org/10.1038/369565a0

  24. Moriyama T, Ohuchida K, Mizumoto K, Cui L, Ikenaga N, Sato N, Tanaka M (2010) Enhanced cell migration and invasion of CD133 + pancreatic cancer cells cocultured with pancreatic stromal cells. Cancer 116:3357–3368. https://doi.org/10.1002/cncr.25121

  25. Morris EJ et al (2013) Discovery of a novel ERK inhibitor with activity in models of acquired resistance to BRAF and MEK inhibitors. Cancer Discov 3:742–750. https://doi.org/10.1158/2159-8290.CD-13-0070

  26. Neyaz A et al (2018) Investigation of targetable predictive and prognostic markers in gallbladder carcinoma. J Gastrointest Oncol 9:111–125. https://doi.org/10.21037/jgo.2017.10.02

  27. Noone AM, Cronin KA, Altekruse SF, Howlader N, Lewis DR, Petkov VI, Penberthy L (2017) Cancer incidence and survival trends by subtype using data from the surveillance epidemiology and end results program, 1992–2013. Cancer Epidemiol Biomark Prev 26:632–641. https://doi.org/10.1158/1055-9965.EPI-16-0520

  28. Palomero T et al (2006) NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth. Proc Natl Acad Sci USA 103:18261–18266. https://doi.org/10.1073/pnas.0606108103

  29. Pikman Y et al (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3:e270. https://doi.org/10.1371/journal.pmed.0030270

  30. Principe DR et al (2017) TGFbeta engages MEK/ERK to differentially regulate benign and malignant pancreas cell function. Oncogene 36:4336–4348. https://doi.org/10.1038/onc.2016.500

  31. Qian BZ et al (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475:222–225. https://doi.org/10.1038/nature10138

  32. Reymond N et al (2012) Cdc42 promotes transendothelial migration of cancer cells through beta1 integrin. J Cell Biol 199:653–668. https://doi.org/10.1083/jcb.201205169

  33. Reymond N, d’Água BB, Ridley AJ (2013) Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13:858–870. https://doi.org/10.1038/nrc3628

  34. Rojnuckarin P, Drachman JG, Kaushansky K (1999) Thrombopoietin-induced activation of the mitogen-activated protein kinase (MAPK) pathway in normal megakaryocytes: role in endomitosis. Blood 94:1273

  35. Rouyez MC, Boucheron C, Gisselbrecht S, Dusanter-Fourt I, Porteu F (1997) Control of thrombopoietin-induced megakaryocytic differentiation by the mitogen-activated protein kinase pathway. Mol Cell Biol 17:4991–5000

  36. Roy LD et al (2011) MUC1 enhances invasiveness of pancreatic cancer cells by inducing epithelial to mesenchymal transition. Oncogene 30:1449–1459. https://doi.org/10.1038/onc.2010.526

  37. Sakamoto A et al (2016) Live-cell single-molecule imaging of the cytokine receptor MPL for analysis of dynamic dimerization. J Mol Cell Biol 8:553–555. https://doi.org/10.1093/jmcb/mjw027

  38. Sangkhae V, Etheridge SL, Kaushansky K, Hitchcock IS (2014) The thrombopoietin receptor, MPL, is critical for development of a JAK2V617F-induced myeloproliferative neoplasm. Blood 124:3956–3963. https://doi.org/10.1182/blood-2014-07-587238

  39. Sato N, Maehara N, Goggins M (2004) Gene expression profiling of tumor–stromal interactions between pancreatic cancer cells and stromal fibroblasts. Cancer Res 64:6950

  40. Sears R, Nuckolls F, Haura E, Taya Y, Tamai K, Nevins JR (2000) Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability. Genes Dev 14:2501–2514

  41. Sheng W et al (2017) Calreticulin promotes EGF-induced EMT in pancreatic cancer cells via Integrin/EGFR-ERK/MAPK signaling pathway. Cell Death Dis 8:e3147. https://doi.org/10.1038/cddis.2017.547

  42. Steeg PS (2006) Tumor metastasis: mechanistic insights and clinical challenges. Nat Med 12:895–904. https://doi.org/10.1038/nm1469

  43. Stewart BW, Wild C, International Agency for Research on Cancer, World Health Organization (2014) World cancer report 2014. International Agency for Research on Cancer

  44. Talmadge JE, Fidler IJ (2010) AACR centennial series: the biology of cancer metastasis: historical perspective. Cancer Res 70:5649–5669. https://doi.org/10.1158/0008-5472.CAN-10-1040

  45. Tichet M et al (2015) Tumour-derived SPARC drives vascular permeability and extravasation through endothelial VCAM1 signalling to promote metastasis. Nat Commun 6:6993. https://doi.org/10.1038/ncomms7993

  46. Tsai WB, Aiba I, Long Y, Lin HK, Feun L, Savaraj N, Kuo MT (2012) Activation of Ras/PI3K/ERK pathway induces c-Myc stabilization to upregulate argininosuccinate synthetase, leading to arginine deiminase resistance in melanoma cells. Cancer Res 72:2622–2633. https://doi.org/10.1158/0008-5472.CAN-11-3605

  47. Vaseva AV et al (2018) KRAS suppression-induced degradation of MYC Is antagonized by a MEK5-ERK5 compensatory. Mech Cancer Cell 34:807–807+. https://doi.org/10.1016/j.ccell.2018.10.001

  48. Wang X, Cunningham M, Zhang X, Tokarz S, Laraway B, Troxell M, Sears RC (2011) Phosphorylation regulates c-Myc’s oncogenic activity in the mammary gland. Cancer Res 71:925–936. https://doi.org/10.1158/0008-5472.CAN-10-1032

  49. Wendel C, Hemping-Bovenkerk A, Krasnyanska J, Mees ST, Kochetkova M, Stoeppeler S, Haier J (2012) CXCR4/CXCL12 participate in extravasation of metastasizing breast cancer cells within the liver in a rat model. PLoS One 7:e30046. https://doi.org/10.1371/journal.pone.0030046

  50. Weng AP et al (2006) c-Myc is an important direct target of Notch1 in T-cell acute lymphoblastic leukemia/lymphoma. Genes Dev 20:2096–2109. https://doi.org/10.1101/gad.1450406

  51. Wu Z et al (2015) TPO-induced metabolic reprogramming drives liver metastasis of colorectal cancer CD110 + tumor-initiating cells. Cell Stem Cell 17:47–59. https://doi.org/10.1016/j.stem.2015.05.016

  52. Yamazaki H, Nishida H, Iwata S, Dang NH, Morimoto C (2009) CD90 and CD110 correlate with cancer stem cell potentials in human T-acute lymphoblastic leukemia cells. Biochem Biophys Res Commun 383:172–177. https://doi.org/10.1016/j.bbrc.2009.03.127

  53. Zabel BA et al (2009) Elucidation of CXCR7-mediated signaling events and inhibition of CXCR4-mediated tumor cell transendothelial migration by CXCR7 ligands. J Immunol 183:3204–3211. https://doi.org/10.4049/jimmunol.0900269

  54. Zheng B et al (2016) CD146 attenuation in cancer-associated fibroblasts promotes pancreatic cancer progression. Mol Carcinog 55:1560–1572. https://doi.org/10.1002/mc.22409

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We are grateful to Emiko Manabe and Shoko Sadatomi (Department of Surgery and Oncology, Kyushu University) for skillful technical assistance. Zilong Yan is the recipient of Rotary Yoneyama Memorial Foundation scholarship [http://www.rotary-yoneyama.or.jp]. We thank Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript. This work was supported by JSPS KAKENHI (Grant number: 26108010, 26293305, 15K10185, 25713050, 16K15621, 16K10601, 16K10600, 16H05417, 15K15498, 15H04933, 16H05418, 17H04284, 17K19602 and 17K19605).

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Correspondence to Kenoki Ohuchida.

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This study was approved by the Kyushu University Institutional Review Board (Fukuoka, Japan).

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Informed consent was obtained from all individual participants included in the study.

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Yan, Z., Ohuchida, K., Zheng, B. et al. CD110 promotes pancreatic cancer progression and its expression is correlated with poor prognosis. J Cancer Res Clin Oncol 145, 1147–1164 (2019). https://doi.org/10.1007/s00432-019-02860-z

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  • Pancreatic cancer
  • CD110
  • TPO
  • Liver metastasis
  • Transendothelial migration